BACKGROUND To evaluate the efficacy of alpha-2b interferon alone or combined with alpha1-thymosin in treatment of patients with chronic hepatitis B (CHB) resistant to lamivudine. METHODS Sixty six patients with CHB resistant to lamivudine were enrolled and randomized into treatment group A, treatment group B and control group. In the treatment group A 26 cases, after giving interferon-alpha alone for 1 month, lamivudine was withdrawn and continuously treated with interferon-alpha for 5 months. In the treatment group B 10 cases, after treatment with interferon-alpha and thymosin-alpha1 for 1 month, lamivudine was withdrawn and continuously treated with interferon-alpha and thymosin-alpha1 for 5 months. In control group (30 cases), after lamivudine was directly withdrawn, no anti-virus drug was given. Hepatic function tests and serum virological index were detected at regular intervals in all patients. RESULTS Normalization rate of hepatic function, HBV DNA seroconversion rate and HBeAg/HBeAb seroconversion rate in two treatment groups were significantly higher than those in control group. CONCLUSIONS The study suggested that interferon-alpha alone or combined with thymosin-alpha1 in treatment of patients with chronic hepatitis B resistant to lamivudine showed a beneficial effect.